Genetic studies indicate that the reovirus proteins sigma3 and mu1 influence the virus-host cell interaction at many stages of pathogenesis, however the specific aspects of protein structure and function which influence those interactions are unknown. We will elucidate the relationships between biological phenotypes that have been mapped to the reovirus S4 and M2 genes and known biochemical properties of their products, sigma3 and mu1, to contribute to our understanding of the molecular basis of viral pathogenesis. The study of the structure and function of reovirus proteins will also provide insight into protein-protein and protein-nucleic acid interactions that will be applicable to more complex biological systems. A variety of evidence suggests that the sigma3 protein is involved in reovirus control of host cell macromolecular synthesis. We will use genetic and biochemical approaches to investigate the mechanisms involved in the control of translation in reovirus infected cells and the role of the sigma3 protein in these mechanisms. We will determine if association with mu1 modulates the ability of sigma3 to function as a regulator of translation and we will identify the molecular determinants which are required for their interaction. The molecular details of entry are not well understood for nonenveloped viruses. Cytoplasmic penetration by reoviruses is mediated by a stable subviral particle which has lost sigma3 and has a cleaved form of mu1. Cleavage of these proteins is an essential step in the reovirus replication cycle. We will investigate the importance of sigma3/mul interaction for protein cleavage and identify the molecular determinants which enable subviral particles to disrupt the integrity of cell membranes.